Piperazino derivatives as neurokinin antagonists

ABSTRACT

The invention relates to compounds of the formulas ##STR1## wherein Z, R c , y, x, l 1 , l 2 , l 3 , u, R 4 ,R c&#39; , n, R 1 , R 2 , and R 3 , are as described herein. These compounds are neurokinin antagonists. These compounds are useful in the treatment of chronic airway diseases such as asthma.

BACKGROUND OF THE INVENTION

The present invention relates to a genus of compounds useful asantagonists of neurokinin receptors. In particular, these can beneurokinin-1 receptor (NK₁) antagonists. Some can also be neurokinin-1receptor (NK₁)antagonists and neurokinin-2 receptor (NK₂) antagonists,that is, NK₁ /NK₂ dual receptor antagonists.

Neurokinin receptors are found in the nervous system and the circulatorysystem and peripheral tissues of mammals, and therefore are involved ina variety of biological processes. Neurokinin receptor antagonists areconsequently expected to be useful in the treatment or prevention ofvarious mammalian disease states, for example asthma, cough,bronchospasm, inflammatory diseases such as arthritis, migraine,nociception, and various gastrointestinal disorders such as Crohn'sdisease.

In particular, NK₁ receptors have been reported to be involved inmicrovascular leakage and mucus secretion, and NK₂ /receptors have beenassociated with smooth muscle contraction, making NK₁ and NK₂ receptorantagonists especially useful in the treatment and prevention of asthma.

SUMMARY OF THE INVENTION

The invention relates to compounds of the formula: ##STR2## wherein eachR₁ is independently ##STR3## and where R_(a) is not H in ##STR4## andeach R₂, and R₃ is independently ##STR5## each R_(a) and R_(b) isindependently selected from the group consisting of H; C₁ -C₆ alkyl,CF₃, C₂ F₅, phenyl, and benzyl;

each R_(c) and R_(c') is selected from the group consisting of H, C₁ -C₆alkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, unsubstituted or substitutedphenyl, and unsubstituted or substituted benzyl, with the proviso thatno more than one R_(c) is other than H in the ##STR6## moiety, and nomore than one R_(c') is other than H in the ##STR7## moiety; R₄ is##STR8## n is 0 to 5; and wherein

l₁ is 0, l₂ is 0, l₃ is 2 to 4,

and x is 0, and y is 2 to 4; or

x is 1, and y is 0 to 3;

or

wherein

l₁ is 0, l₂ is l₃ is 1 to 3,

and x is 0, and y is 2 to 5;

or

wherein

l₁ is 1 to 3, l₂ is 1, l₃ is 0,

and x is 0, and y is 2 to 4; or

x is 1, and y is 0 to 3;

Z is selected from the group consisting of ##STR9## m₁ is 1 to 2; n₁ is1 to 2;

m₂ is 0 to 2;

n₂ is 1 to 2;

p₁ and p₂ are each independently 1 to 4 with the proviso that p₁ and p₂added together are 2 to 6;

q₁ and q₂ are integers and each is independently 0 to 4 with the provisothat q₁ and q₂ added together equal 3 to 5;

r₁ and r₂ each is independently 0 to 4, with the proviso that r₁ and r₂added together are 3 to 5;

each t is 0 to 4;

each u is independently 0 to 2; and

R₅ is selected from the group consisting of ##STR10## wherein R_(a) isnot H when R₅ is ##STR11## and with the proviso that when R₅ is C₃ -C₆alkenyl or C₃ -C₆ alkynyl, the double or triple bond cannot be directlyattached to nitrogen;

R₆ is selected from the group consisting of ##STR12## R₇, and R₈ areeach independently selected from the group consisting of ##STR13## R₇,and R₈ are each independently selected from the group consisting of##STR14## and wherein R₇ and R₈ can be bonded to the same carbon atom,or R₇ and R₈ taken together can be a carbonyl group;

and with the proviso that no two groups selected from the groupconsisting of --OR_(a) and --N(R_(a),R_(b)), can be bonded to the samecarbon atom, and with the further proviso that no group selected fromthe group consisting of --OR_(a) and --N(R_(a),R_(b)), can be bonded toa carbon adjacent to a nitrogen atom;

R₉ is selected from the group consisting of ##STR15## wherein R_(a) isnot H, when R₉ is ##STR16## and wherein substituted means 1 to 3substituents independently selected from the group consisting of H, C₁-C₆ alkyl, CF₃, C₂ F₅, OH, OC₁ -C₆ alkyl, Cl, Br, I and F;

or a pharmaceutically acceptable salt thereof.

Preferred compounds of the invention are compounds of formula I wherein

l₁ is 0, l₂ is 0, l₃ is 2 to 4, and n is 0 to 5;

and x is 0, and y is 2 to 4; or

x is 1, and y is 0 to 3.

Preferred compounds of the invention are compounds of formula I

wherein

l₁ is 0, l₂ is 1, l₃ is 1 to 3,

and n is 1 to 5,

and x is 0, and y is 2 to 5.

Preferred compounds of the invention are compounds of formula I asdescribed above wherein l₃ is 1.

Preferred compounds of the invention are compounds of formula I

wherein

l₁ is 1 to 3, l₂ is 1, l₃ is 0,

n is 1 to 5;

and x is 0, and y is 2 to 4; or

x is 1, and y is 0 to 3;

A compound according to formula I wherein one of R₁, R₂, and R₃ in the##STR17## moiety of formula I is H. A compound according to formula Iwherein two of R₁, R₂, and R₃ in the ##STR18## moiety of formula I is H.

A compound according to formula I wherein all of R_(c) or all of R_(c')are H.

A compound according to formula I wherein R₄ is phenyl or ##STR19##wherein each R₁ is independently ##STR20## and where R_(a) is not H in##STR21## and each R₂, and R₃ can be independently ##STR22## and eachR_(a) and R_(b) is independently selected from the group consisting ofH; C₁ -C₆ alkyl, CF₃, C₂ F₅, phenyl, and benzyl.

A compound according to formula I wherein Z is ##STR23##

A compound according to formula I wherein Z is ##STR24##

A compound according to formula I wherein Z is ##STR25##

A compound according to formula I wherein Z is ##STR26##

A compound according to formula I wherein R₅ is H, C₁ -C₅ alkyl, or##STR27##

A compound according to formula I wherein R₆ is H, C₁ -C₅ alkyl, or##STR28##

A compound according to formula I wherein R₇ is H, C₁ -C₅ alkyl, or##STR29##

A compound according to formula I wherein R₈ is H, C₁ -C₅ alkyl, or##STR30##

A compound according to formula I wherein R₉ is H, C₁ -C₅ alkyl, or##STR31##

A compound according to formula I wherein one of R₁, R₂, R₃ is H, Z isQ, R, or S all of R_(c) and R_(c') are H and R₄ is substituted orunsubstituted phenyl, l₁ and l₂ are 0-3 is 2; x, y, and n are 1; and uis 0.

Exemplary compounds of the invention are compounds of the formulas:

A compound selected from the group consisting of ##STR32## or a compoundselected from the group consisting of ##STR33## wherein Z is ##STR34##or a compound selected from the group consisting of ##STR35## or acompound selected from the group consisting of ##STR36## or a compoundselected from the group consisting of ##STR37## or a compound selectedfrom the group consisting of ##STR38## wherein Z is ##STR39## or acompound selected from the group consisting of ##STR40## or a compoundselected from the group consisting of ##STR41## wherein Ar is ##STR42##and wherein X is and Y is ##STR43## or a compound selected from thegroup consisting of ##STR44## wherein Ar is ##STR45## wherein X is and Yis ##STR46## or a compound selected from the group consisting of##STR47## wherein Ar is phenyl or 3, 4-dichlorophenyl wherein A is and Zis ##STR48## or a compound selected from the group consisting of##STR49## wherein X is ##STR50## and wherein X is and Y is ##STR51## ora compound selected from the group consisting of ##STR52## wherein Ar is##STR53## and wherein X is and Y is ##STR54## or a compound selectedfrom the group consisting of ##STR55## wherein Ar is ##STR56## andwherein X is and Y is ##STR57## or a compound selected from the groupconsisting of ##STR58## wherein Ar is or ##STR59## and wherein X is and##STR60## or a pharmaceutically acceptable salt thereof.

The invention also relates to a pharmaceutical composition comprising athereapeutically effective amount of a compound of formula I incombination with a pharmaceutically acceptable carrier.

The invention also relates to a method for treating chronic airwaydiseases such as asthma and allergies; inflammatory diseases such asinflammatory bowel disease, psoriasis, fibrositos, osteoarthritis, andrheumatoid arthritis; migraine; central nervous system disorders such asdepression, psychosis, dementia, and Alzheimer's disease; Down'ssyndrome; neuropathy; multiple sclerosis; ophthalmic disorders;conjunctivitis; auto immune disorders; graft rejection; systemic lupuserythematosus; GI disorders such as Crohn's disease and ulcerativecoliris; disorders of bladder function; circulatory disorders such asangina; Raynaud's disease; coughing and pain. In particular, theinvention also relates to a method of treating asthma which comprisesadministering to a mammal in need of such treatment an anti-asthmaeffective amount of a compound of formula I for such purpose.

DETAILED DESCRIPTION OF THE INVENTION

As used herein the term alkyl means a straight or branched, saturatedhydrocarbon chain having from 1 to 6 carbon atoms. The number of carbonatoms may be designated. For example, "C₁ -C₆ alkyl" represents astraight or branched, saturated hydrocarbon having from 1 to 6 carbonatoms.

The term alkenyl means means a straight or branched, saturated alkenylhaving from 2 to 6 carbon atoms. The number of carbon atoms may bedesignated. For example, "C₂ -C₆ alkenyl" represents a straight orbranched alkenyl having from 1 to 6 carbon atoms.

The term alkynyl means a straight or branched, saturated alkynyl havingfrom 2 to 6 carbon atoms. The number of carbon atoms may be designated.For example, "C₂ -C₆ alkynyl" represents a straight or branched chainalkynyl having from 2 to 6 carbon atoms.

As used herein, a heavy dark line () denotes a chemical bond comingabove the plane of the page. A dashed line () denotes a chemical bondcoming below the plane of the page.

As used herein, ##STR61## for example, means that R₁, R₂, and R₃ can bein either of the rings of the above naphthyl moiety.

Asymetric centers exist in compounds of formula I of the invention.Accordingly, compounds of formula I include stereoisomers.

All such isomeric forms and mixtures thereof are within the scope of thepresent invention. Unless otherwise indicated, the methods ofpreparation disclosed herein may result in product distributions whichinclude all possible structural isomers, although it is understood thatphysiological response may vary according to stereochemical structure.The isomers may be separated by conventional means such as fractionalcrystallization, preparative plate or column chromatography on silica,alumina, or reversed phase supports or HPLC (high performance liquidchromatography).

Enantiomers may be separated, where appropriate, by derivatization orsalt formation with an optically pure reagent, followed by separation byone of the aforementioned methods. Alternatively, enantiomers may beseparated by chromatography on a chiral support.

The compounds of formula I can exist in unsolvated as well as solvatedforms, including hydrated forms, e.g. the hemihydrate. In general, thesolvated forms, with pharmaceutically acceptable solvents such as water,ethanol, and the like are equivalent to the unsolvated forms for thepurposes of the invention.

Those compounds of formula I which contain a basic group such as --CH₂NH₂, form pharmaceutically acceptable salts. The preferredpharmaceutically acceptable salts are nontoxic acid addition saltsformed by adding to a suitable compound of the invention about astoichiometric amount of a mineral acid, such as HCl, HBr, H₂ SO₄ or H₃PO₄ or of an organic acid such as acetic, propionic, valeric, oleic,palmitic, stearic, lauric, benzoic, lactic, para-toluenesulfonic,methane sulfonic, citric, maleic, fumaric, succinic and the like,respectively.

General Methods of Preparation

The compounds of this invention may be prepared by one of the followinggeneral methods. As used herein RT means room temperature. Unlessotherwise indicated, variables in the structural formulas below are asdefined above.

Method 1.

If the group R₄ is an aromatic group with no l or Br substituents, l₁and l₂ are all 0, and l₃ is 2, then the following method may be used toprepare the useful intermediates (IV): ##STR62##

Transition metal catalyzed coupling of 2-chloropyrazine with an aromaticGrignard reagent in a dry, ether solvent, such as THF, yields thearyl-substituted pyrazine of formula II'. The catalyst shown,1,2-bis-(diphenylphosphino)ethane!nickel^(II) chloride, is a preferredreagent for this transformation. Where R₄ has no halo substituents,reduction of a compound of formula II' by catalytic hydrogenation,using, for instance, palladium acetate, preferably in acetic acidsolvent, results in preferential reduction of the pyrazine ring, leavingthe aromatic ring unreduced, that is, it results in a compound offormula II. Similarly, 10% Pd on charcoal (Pd-C) can be used in analcohol solvent, preferably methanol, with or without the addition of asmall quantity (1 to 5 equivalents.) of acetic acid. Reaction times offrom 1 to 24 hours generally suffice for this reaction, which ispreferentially run at room temperature or slightly above (up to about50° C.) and using from 1 to about 6 atmospheres pressure of hydrogen.##STR63##

The intermediate of formula II may also be prepared from a compound offormula II', even if the group R₄ contains halogen atoms, by reductionusing a strong hydride ion donor, preferably lithium aluminum hydride(LAH) or diisobutyl aluminum hydrate (DIBAL-H) in an ether solvent, suchas ether, THF or dimethoxyethane (DME).

Selective alkylation of a compound of formula II is possible using lowtemperature conditions. Thus, reacting a compound of formula II with asubstituted aryl-alkyl halide of formula III results in the formation ofthe 4-substituted derivative of formula IV. Suitable conditions includeuse of a halogenated solvent, such as CH₂ Cl₂, at low temperature.Suitable temperatures are from -78° C. initially, allowing the reactionmixture to warm gradually to RT if the reaction is not completed afterseveral hours. The reaction is catalyzed by the addition of anequivalent amount of an organic base, such as triethylamine anddiisopropylethylamine (Hunig's base). ##STR64##

Method 2.

If the group R₄ contains one or more halogen atoms on an aromatic ringand the other groups are as in Method 1, then an alternate route to acompound of formula IV is preferred. In addition, this method can beused to prepare compounds in which l₁ and 1₂ are both zero, and l₃ isfrom 2 to 4. Mono-protection of the diamine of formula (A), preferablywith BOC anhydride, or other agents known to introduce thet-butyloxycarbonyl protecting group, in an alcohol solvent, such asmethanol, preferably at about -10° C., produces a compound of formula V.##STR65##

These compounds are used to perform a reductive amination reaction withthe aldehyde of formula VI to produce an amine of formula VII.

Suitable conditions for this type of reaction include the use of analcohol solvent, preferably methanol, made slightly acidic with a weakorganic acid, such as acetic acid, and a reducing agent known to favorreductive amination reactions, preferably sodium cyanoborohydride, NaBH₃CN. ##STR66##

Reaction of a compound of formula VII with a phenacyl halide derivativeof formula VIII, in which R₄ preferably represents a halogenatedaromatic ring, but may be any of the claimed aromatic rings, in thepresence of an organic base, such as di-isopropylethylamine, also knownas Hunig's Base, in an ether solvent, such as THF, results in theformation of the intermediates of formula IX. ##STR67##

Removal of the BOC protecting group using a suitable acidic catalyst,such as trifluoroacetic acid, followed by an intramolecular reductiveamination, under conditions such as those described above for thepreparation of a compound of formula VII, leads to the formation ofcompounds of formula IVA. ##STR68##

Method 3.

An alternate route to compounds of the invention in which l₁, l₂ and mare 0, and l₃ is 2 is as follows. Standard coupling of an N-protectedamino acid of formula X, wherein such as R₄ -CH(NHProt)CO₂ H, with aglycine ester, (for instance the ethyl ester of formula XI), produces adipeptide of formula XII. A suitable protecting group is BOC, althoughmany others may also be used. Other esters of glycine may also be used.Standard coupling techniques may be applied, an example being the use ofN-hydroxybenztriazole (HOBT) and a water-soluble carbodiimide, such as1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (DEC), in a non-hydroxylicsolvent such as DMF or DMA. The reaction is run, preferably, at or belowRT, and takes from 1 to 40 hours for completion, depending upon thesubstrates. ##STR69##

Removal of the protecting group under standard conditions, followed bytreatment of the product with a base results in cyclization to thediketopiperazine of formula XIII. Suitable conditions for removal of theexemplified BOC group are well known in the art and include catalysis bytrifluoroacetic acid (TFA). A suitable base for cyclization is thealkali metal salt of an alcohol in the alcohol itself used as solvent.For example, a solution of sodium ethoxide in ethanol may be used. Thetemperature is preferably around RT but may be slightly above or below,in the range 0° C. to about 40° C. The reaction is generally completewithin a few hours. Suitable reaction times are from 1 to 24 hours.##STR70##

Reduction of the diketopiperazine of formula XIII may be accomplishedpreferentially with a strong hydride reducing agent, such as LAH or asolution of sodium bis(2-methoxyethoxy)aluminum hydride in toluene (alsoknown as Red-Al®). Suitable solvents for this reaction are DME and otherhigher boiling ethers since the reaction is run at elevatedtemperatures, from about 50° C. to about 110° C., preferably at about90° C. ##STR71##

A compound of formula II may be converted to a compound of formula IV bythe processes described in Method 1.

Method 4.

The intermediates of formula IV or IVA, formed via any of the previousmethods, may be further processed as follows. A compound of formula IVwill be used in the Schemes but it should be understood that compoundsof formula IVA may also be used in the same way. Reaction of a compoundof formula IV with an activated halo-acid, generally the acid halide offormula XIV, in which Hal represents Cl, Br, or I, yields the acylatedderivative of formula XV. An organic base is used to take up thehydrogen halide formed in the reaction, suitable bases beingtriethylamine (TEA) and Hunig's Base. Suitable reaction media includehalogenated solvents, such as methylene chloride and chloroform. Thereaction is preferably run at low temperature, at least initially.Suitable temperatures are in the region of -50° C. down to -80° C. Laterin the reaction it may be desirable to allow the mixture to warm up toabout RT to ensure completion of the reaction. ##STR72##

Reaction of the halogenated amides of formula XV with an amine offormula Z--H results in formation of the products of formula XVI, whichare compounds of the invention. Compounds of formula of XVI have beenmodified to show the fact that these products could have been preparedfrom compounds of formula IVA as well as from IV. Suitable solvents forthis reaction are halogenated hydrocarbons, such as methylene chloride,and an organic base is present to absorb the H-Hal formed. Appropriatebases include Hunig's Base. The reaction is performed at or around RT, asuitable temperature being generally in the range of from 0° C. to 40°C. Reaction is complete within 1 to 48 hours. ##STR73##

Method 5.

Compounds of formula XVI where y≠0 may be converted to other compoundsof the invention of formula XVII by reduction under controlledconditions. It should be realized that the value of y is different informulas XVI and XVII. In formula XVI, where x=1, y=1 to 4, but informula XVII, where x=0, y=2 to 5. ##STR74##

Suitable reducing agents to effect this transformation include theborane-dimethyl sulfide complex, as well as other less selectivereagents, such as LAH, (assuming that no other group reactive to LAH ispresent), Red-Al®, and diborane in ether. Effective temperatures for theborane-dimethylsulfide complex to reduce compounds of formula XVI, rangefrom RT to the reflux temperature of the solution of the reagent in THF(about 80° C.).

Method 6.

Intermediates of the formula XVIII may be selectively acylated bycoupling with an acid of the formula XIX. Standard coupling techniquesmay be applied, an example being the use of HOBT, a water-solublecarbodiimide, such as DEC, and an organic base, such as triethylamine,in a non-hydroxylic solvent, such as CH₂ Cl₂, at a temperature of about-20° C. initially. The mixture may be allowed to warm to RT to completethe reaction. The product of reaction is the amide of formula XX.##STR75##

Compounds of the formula XX, may be further acylated using an acidhalide of formula XXI. The reaction is run, preferably at about -78° C.,over a period of 1 to 12 hours, in a halogenated solvent, such asmethylene chloride or similar solvent. An organic tertiary amine is usedto absorb the H-Hal produced in the reaction. Suitable amines includetriethylamine and Hunig's Base. ##STR76##

The compounds of formula XXI may be used for further reaction withoutisolation. Additional organic base, for instance, Hunig's Base, is addedto the mixture followed by Z--H, at around -78° C. The reaction iscompleted by allowing the mixture to warm to RT overnight yielding thecompounds of formula XXII after work-up and purification by standardmethods. ##STR77##

The compounds of formula XXII, in which y≠0 may be converted to othercompounds of the invention of formula XXIII by reduction undercontrolled conditions. It should be realized that the value of n and yare different in compounds of formulas XXII and XXIII. In of formulaXXII, where x=1, n=0-4 and y=1 -4. In formula XXIII, where x=0, n=1 -5and y=2 -5. ##STR78##

Suitable reducing agents to effect this transformation include theborane-methyl sulfide complex, as well as other less selective reagents,such as LAH, Red-AI®, and diborane in ether or other unreactivesolvents, such as THF. Using the borane-methyl sulfide complex in THF,at the reflux temperature of the solution, which is about 80° C., thereaction is complete in about 2 hours to 48 hours depending on theprecise substrate.

Method 7.

The acylated derivatives of formula XX from Method 6 may be reduced tothe saturated alkyl chain derivatives of formula XXIV. As in previousreactions where a carbonyl group is reduced to a --CH₂ -- group thevalue of n is different in starting material and product. In formula XXwhere n=0-4, whereas in formula XXIV where n=1-5. ##STR79##

The process to conduct this conversion is the same as described inMethod 6 for conversion a compound of formula XXII to a compound offormula XXIII. The reagent of preference is the boranemethyl sulfidecomplex.

Reaction of the intermediate of formula XXIV with the acyl halide offormula XXV at temperatures of about -78° C. produces the amides offormula XXVI. The reaction is run in a halogenated solvent, such asmethylene chloride, in the presence of an organic base to take up theH-Hal formed. A suitable base is Hunig's Base. This product may be usedwithout isolation in the subsequent step. ##STR80##

The halo-derivative of formula XXVI may be used without isolation toreact with the amine compound of formula Z--H. An additional equivalentamount of a suitable organic base, such as Hunig's Base, is added to themixture to consume H-Hal. The reaction is initially run at about -78° C.but is allowed to warm gradually to RT to complete the reaction. Theproduct, compound of formula XXVII, is isolated by conventionaltechniques and may be purified by flash chromatography. ##STR81##

Method 8.

For compounds of Claim 1 in which l₁ is 1 -3, l₂ is 1, and l₃ is 0 thefollowing scheme may be used. Reaction of the protected amino acid offormula XXVIII with the amino-alcohol of formula XXIX yields theprotected amide compound of formula XXX. A suitable protecting group isthe BOC group, which is known to be resistant to hydrolysis under basicconditions. Others, such as the carbobenzyloxy (Cbz) group may also beused. Coupling conditions similar to those employed in Method 3(HOBT/DEC) may be used to effect this coupling reaction. ##STR82##

Cyclization of a compound of formula XXX may be accomplished withconcomitant loss of the protecting group. Warming a compound of formulaXXX with a mixture of acetic acid or trifluoroacetic acid and aceticanhydride results in cyclization with loss of the protecting group toproduce a compound of formula XXXI. Suitable temperatures for thisreaction are from 40° C. to 100° C. ##STR83##

Protection of the amine nitrogen of formula XXXI is then accomplishedunder standard conditions. Suitable reagents include di-t-butyldicarbonate, to produce the BOC derivative, and benzyl chloroformate toproduce the Cbz derivative. Other protecting groups, made under standardconditions may also be used. Alkylation of the amide is carried outusing one of a variety of conditions. Representative reagents for theconversion of a compound of formula XXXII to a compound of formulaXXXIII, using the alkylating agent of formula XXXIV, or an equivalent,such as the mesylate or tosylate instead of the Hal derivative, includeNaH in DMF or DMA, and anhydrous K₂ CO₃ or Cs₂ CO₃ in DMF. Suitabletemperatures for the reaction with NaH are from 0° C. to 50° C., and forthe other reagents from RT to about 120° C., depending on the precisesubstrates. ##STR84##

Removal of the protecting group under standard conditions then releasesthe free amine of formula XXXV which may be acylated at low temperature,for instance, as described in Method 4, using the halo-acid halide offormula XXXVI to produce the halo-derivative of formula XXXVII. Thisproduct may be used without isolation for the next step. ##STR85##

Treatment of the halo-derivative of formula XXXVII with Z--H in thepresence of an organic base, under the same conditions as described inMethod 6, results in products of formula XXXVIII which are compounds ofthe invention. ##STR86##

Method 9.

Reaction of a 2-substituted ethylene diamine of formula XXXIX with anα-halo-ester of formula XL in the presence of an organic base, such asHunig's Base, results in the formation, preferentially, of thederivative of formula XL. The reaction is run at as low a temperature aspossible conducive with a reasonable reaction rate. Temperatures in therange of -20° C. to 40° C. are preferred. Cyclization of thisintermediate under basic conditions produces the ring system of acompound of formula XLII. In a compound of formula XL, the esterfunction, there defined as ethyl, may be any readily available esterthat is not highly sterically hindered, such as methyl, n-propyl, orbenzyl, instead of ethyl. A compound of formula XLI may be separatedfrom any isomeric product, formed by reaction with the more hinderedamino group, by conventional means, such as crystallization or flashchromatography. Suitable bases for the cyclization include alkali metalalkoxides in the respective alcohol, for example, sodium ethoxide inethanol. ##STR87##

A compound of formula XLII may be alkylated using the reagent of formulaXLV, in which L is a suitable leaving group, such as Cl, Br, I,mesylate, or tosylate, to yield product of formula XLVI. The reactionmixture also includes an organic base to absorb H--L during thereaction. Suitable bases include triethylamine and Hunig's Base. Thereaction is run at temperatures from below RT (0° C.) to about 40° C.depending upon the specific substrate. ##STR88##

The compounds of formula XLVI may be further alkylated, under moresevere conditions, on the nitrogen of the amide, yielding compounds offormula XLVIII respectively. The protected aldehydes of formula XLIX maybe used in this reaction to introduce the chain of atoms --(CH₂)y⁻.However, it should be noted that the value for y is different from thedefinition in Claim 1. This is because the carbon of the protectedaldehyde will eventually form a part of the chain between the nitrogenatom and the Z-group. Thus, in the reagent of formula XLIX, as well asin the product compound of formula XLVII, y=1 to 4 instead of 2 to 5.Suitable conditions for these alkylation reactions include the use ofsodium hydride as base, followed by the alkylating agent, or the use ofan alkali metal carbonate, especially potassium or cesium carbonate.Both types of reagent may be used in DMF or DMA solution. NaH may alsobe used in solution in an ether, such as THF or 1,2-dimethoxyethane.##STR89##

The acetal protecting group may next be removed by reaction with anacidic reagent, such as HCl/dioxane, to produce the aldehydes of formulaLI. ##STR90##

The aldehydes of formula LI may now be modified by the introduction ofthe group Z--. This may be accomplished by a reductive alkylation of theamine Z--H with the aldehydes under standard conditions. Such conditionsare exemplified by the use of sodium cyanoborohydride in an alcoholsolvent, preferably methanol, at a reaction temperature between about 0°C. and RT. Products of these reactions are compounds of the invention offormula LIII where y is now the same as defined in Claim 1, that is 2-5.##STR91##

Controlled alkylation of compounds of formula XLVI using adifferentially activated alkylene dihalide of formula LIV, in which Hal₁is chloro and Hal₂ is either bromo or iodo, produces the haloalkylderivatives of formula LVI. Suitable bases for this transformationinclude NaH in DMF, DMA, or THF. ##STR92##

Reaction of these halogen compounds with the amine Z--H is carried outusing an organic tertiary amine to absorb the H-Hal₁. Suitable basesinclude Hunig's Base. However, it is well known that if Hal₁ is achlorine atom that it is not easily displaced, it is often preferable toreplace the chlorine by, preferably, an iodine atom. This may beachieved by treating the compounds of formula LVI with a solution of Nalor KI in acetone or a higher ketone, such as methyl ethyl ketone ormethyl iso-butyl ketone, and heating the solution to a temperaturebetween RT and the boiling point of the solvent in use. Conditions maybe adjusted to suit the particular substrate. Subsequent treatment ofthe exchanged halogen product with the amine Z--H, as described above,leads to the products of formula LVIII which are compounds of theinvention. ##STR93##

The in vitro and in vivo activity of the compounds of formula I can bedetermined by the following procedures.

In vitro procedure to identify NK₁ activity

Test compounds are evaluated for their ability to inhibit the activityof the NK₁ agonist Substance P on the isolated guinea pig vas deferens.Freshly cut vas deferens are removed from male Hartley guinea pigs(230-350 g) and suspended in 25 ml tissue baths containing Kreb'sHenseleit solution warmed to 37° C. and constantly aerated with 95% O₂and 5% CO₂. Tissues are adjusted to 0.5 g and allowed to equilibrate fora period of 30 minutes. The vas deferens are exposed to an electricalfield stimulation (Grass S48 Stimulator) every 60 seconds at anintensity that will cause the tissue to contract 80% of its maximumcapacity. All responses are recorded isometrically by means of a Grassforce displacement transducer (FT03) and Harvard electronic recorder.Substance P inhibits the electrical field stimulated-inducedcontractions of the guinea pig vas deferens. In unpaired studies, alltissues (control or drug treated) are exposed to cumulativeconcentrations of Substance P (1×10⁻¹⁰ M-7×10⁻⁷ M). Singlelog-concentrations of the test compounds are given to separate tissuesand allowed to equilibrate for 30 minutes before a Substance Pconcentration-response curve is generated. At least 5 separate tissuesare used for each control and individual drug-concentration for everydrug assay.

Inhibition of the Substance P is demonstrated by a rightward shift ofits concentration-response curve. These shifts are used to determine thepA₂ value, which is defined as the negative log of the molarconcentration of the inhibitor which would require that twice as muchagonist be used to elicit a chosen response. This value is used todetermine relative antagonist potency.

Isolated Hamster Trachea NK₂ Assay

General methodology and characterization of hamster trachea responses toneurokinin agonists as providing an NK₂ monoreceptor assay is found inC. A. Maggi, et al., Eur. J. Pharmacol. 166 (1989) 435 and J. L. Ellis,et al., J. Pharm. Exp. Ther. 267 (1993) 95.

Continuous isometric tension monitoring is achieved with Grass FT-03force displacement transducers connected to Buxco Electronicspreamplifiers built into a Graphtec Linearcorder Model WR 3310.

Male Charles River LAK:LVG (SYR) hamsters, 100-200 g fed weight, arestunned by a sharp blow to the head, loss of corneal reflex is assured,the hamsters are sacrificed by thoractomy and cutting the heart.Cervical trachea segments are removed to room temperature Krebs buffer,pH 7.4, aerated with 95% O₂₋₅ % CO₂ gas and cleaned of adhering tissue.The segments are cut into two 3-4 mm long ring segments. Tracheal ringsare suspended from transducers and anchored in 15.0 ml water jacketedorgan baths by means of stainless steel hooks and 6-0 silk. Baths arefilled with Krebs buffer, pH 7.4, maintained at 37° C. and continuouslyaerated with 95% O₂₋₅ % CO₂ gas. Tracheal rings are placed under 1.0 ginitial tension and allowed a 90 min equilibration period with four 1 μMNKA challenge, wash and recovery cycles at 20 min intervals. 30 minvehicle pretreatment is followed by cumulative additions of rising dosesof NKA (3 nM-1 μM final concentration, 5 min intervals betweenadditions). The final NKA response is followed by a 15 min wash andrecovery period. 30 min pretreatment with a test compound or its vehicleis followed by cumulative additions of rising doses of NKA (3 nM-10 μMfinal concentration if necessary, 5 min intervals between additions).The final NKA response is followed by a 1 mM carbachol challenge toobtain a maximal tension response in each tissue.

Tissue responses to NKA are recorded as positive pen displacements overbaseline and converted to grams tension by comparison to standardweights. Responses are normalized as a % of the maximal tissue tension.ED₅₀ 's are calculated for NKA from the control and treated NKA doseresponses and compared. Test compounds resulting in an agonist doseratio ≧2 at a screening concentration of 1 μM (i.e. pA₂≧ =6.0) areconsidered actives. Further dose response data is obtained for activesso that an apparent pA₂ estimate can be calculated. pA₂ is calculatedeither by estimation of K_(i) as described by Furchgott (where pA₂ =-LogK_(i), R. F. Furchgott, Pharm. Rev. 7 1995! 183) or by Shild PlotAnalysis (O. Arunlakshana & H. O. Shild, Br. J. Pharmacol. 14 1959! 48)if the data is sufficient.

Effect of NK₁ Antagonists on Substance P-Induced Airway MicrovascularLeakage in Guinea Pigs

Studies are performed on male Hartley guinea pigs ranging in weight from400-650 g. The animals are given food and water ad libitum. The animalsare anesthetized by intraperitoneal injection of dialurethane(containing 0.1 g/ml diailylbarbituric acid, 0.4 g/ml ethylurea and 0.4g/ml urethane). The trachea is cannulated just below the larynx and theanimals are ventilated (V_(T) =4 ml, f=45 breaths/min) with a Harvardrodent respirator. The jugular vein is cannulated for the injection ofdrugs.

The Evans blue dye technique (Danko, G. et al., Pharmacol. Commun.,1,203-209, 1992) is used to measure airway microvascular leakage (AML).Evans blue (30 mg/kg) is injected intravenously, followed 1 min later byi.v. injection of substance P (10 μg/kg). Five min later, the thorax isopended and a blunt-ended 13-guage needle passed into the aorta. Anincision is made in the right atrium and blood is expelled by flushing100 ml of saline through the aortic catheter. The lungs and trachea areremoved en-bloc and the trachea and bronchi are then blotted dry withfilter paper and weighed. Evans blue is extracted by incubation of thetissue at 37° C. for 18 hr in 2 ml of formamide in stoppered tubes. Theabsorbance of the formamide extracts of dye is measured at 620 nm. Theamount of dye is calculated by interpolation from a standard curve ofEvans blue in the range 0.5-10 μg/ml in formamide. The dye concentrationis expressed as ng dye per mg tissue wet weight. Test compounds weresuspended in cyclodextran vehicle and given i.v. 5 min before substanceP.

Measurement of NK₂ Activity In Vivo

Male Hartley guinea pigs (400-500 gm) with ad lib. access to food andwater are anesthetized with an intraperitoneal injection of 0.9 ml/kgdialurethane (containing 0.1 g/m diallylbarbituric acid, 0.4 g/mlethylurea and 0.4 g/ml urethane). After induction of a surgical plane ofanesthesia, tracheal, esophageal and jugular venous cannulae areimplanted to facilitate mechanical respiration, measurement ofesophageal pressure and administration of drugs, respectively.

The guinea pigs are placed inside a whole body plethysmograph and thecatheters connected to outlet ports in the plethysmograph wall. Airflowis measured using a differential pressure transducer (Validyne,Northridge Calif., model MP45-1, range ±2 cmH₂ O) which measures thepressure across a wire mesh screen that covers a 1 inch hole in the wallof the plethysmograph. The airflow signal is electrically integrated toa signal proportional to volume. Transpulmonary pressure is measured asthe pressure difference between the trachea and the esophagus using adifferential pressure transducer (Validyne, Northridge, Calif., modelMP45-1, range ±20 cm H₂ O). The volume, airflow and transpulmonarypressure signals are monitored by means of a pulmonary analysis computer(Buxco Electronics, Sharon, Conn., model 6) and used for the derivationof pulmonary resistance (R_(L)) and dynamic lung compliance (C_(Dyn)).

Bronchoconstriction Due to NKA

Increasing iv doses of NKA are administered at half log (0.01-3 μg/kg)intervals allowing recovery to baseline pulmonary mechanics between eachdose. Peak bronchoconstriction occurs within 30 seconds after each doseof agonist. The dose response is stopped when C_(Dyn) is reduced 80-90%from baseline. One dose-response to NKA is performed in each animal.Test compounds are suspended in cyclodextran vehicle and given i.v. 5min before the initiation of the NKA dose response.

For each animal, dose response curves to NKA are constructed by plottingthe percent increase in R_(L) or decrease in C_(Dyn) against log dose ofagonist. The doses of NKA that increased R_(L) by 100% (R_(L) 100) ordecreased C_(Dyn) by 40% (C_(Dyn) 40) from baseline values are obtainedby log-linear interpolation of the dose response curves.

Neurokinin Receptor Binding Assay(s)

Chinese Hamster ovary (CHO) cells transfected with the coding regionsfor the human neurokinin 1(NK₁) of the human neurokinin 2(NK₂) receptorsare grown in Dulbecco's minimal essential medium supplemented with 10%fetal calf serum, 0.1 mM non-essential amino acids, 2 mM glutamine,100units/ml of penicillin and streptomycin, and 0.8 mg of G418/ml at 37°C. in a humidified atmosphere containing 5% CO₂.

Cells are detached from T-175 flasks with a sterile solution containing5mM EDTA in phosphate buffered saline. Cells are harvested bycentrifugation and washed in RPMI media at 40° C. for 5 minutes. Thepellet is resuspended in Tris-HCl (pH7.4) containing 1 uM phsphoramidonand 4 ug/ml of chymostatin at a cell density of 30×10⁶ cells/ml. Thesuspension is then homogenized in a Brinkman Polytron (setting 5) for30-45 seconds. The homogenate is centrifuged at 800×g for 5 min at 4° C.to collect unbroken cells and nuclei. The supernatant is centrifuged ina Sorvall RC5C at 19,000 rpm (44,00×g) for 30 min at 4° C. The pellet isresuspended, an aliquot is removed for a protein determination (BCA) andwashed again. The resulting pellet is stored at -80° C.

To assay receptor binding, 50 μl of ³ H!-Substance P (9-Sar, 11-Met 02!)(specific activity 41 Ci/mmol) (Dupont-NEN) (0.8 nM for the NK-1 assay)or ³ H!-Neurokinin A (specific activity 114 Ci/mmole) (Zenca) (1.0 nMfor the NK-2 assay) is added to tubes containing buffer (50 mM Tris-HCl(pH 7.4) with 1 mM MnCl₂ and 0.2% Bovine Serum Albumin) and either DMSOor test compound. Binding is initiated by the addition of 100 μl ofmembrane (10-20 μg) containing the human NK-1 or NK-2 receptor in afinal volume of 200 μl. After 40 minutes at room temperature, thereaction is stopped by rapid filtration onto Whatman GF/C filters whichhave been presoaked in 0.3% polyethylenimine. Filters are washed 2 timeswith 3 ml of 50 mM Tris-HCl (pH7.4). Filters are added to 6 mls ofReady-Safe liquid scintillation cocktail and quantified by liquidscintillation spectrometry in a LKB 1219 RackBeta counter. Non-specificbinding is determined by the addition of either 1 μM of CP-99994 (NK₁)or 1 μM SR-48968 (NK₂) (both synthesized by the chemistry department ofScheringPlough Research Institute). IC₅₀ values are determined fromcompetition binding curves and Ki values are determined according toCheng and Prusoff using the experimentally determined value of 0.8 nMfor the NK₁ receptor and 2.4 nM for the NK2 receptor.

Using the test procedures described above, the following data wereobtained for representative compounds of formula I:

For all of the compounds of the invention, the NK₁ binding is in a rangeof about 10-93% inhibition at 1 μM concentration. For all of thecompounds of the invention, the NK₂ binding is in a range of about 0-70%inhibition at 1 μM concentration. It should be understood that while theNK₂ binding for certain compounds of the invention is as low as 0% at 1μM concentration, that at higher concentrations these compounds may haveNK₂ binding inhibition activity.

Representative values for compounds of the invention are as follows:##STR94## has a K_(i) for NK₁ binding, of 136 nM; and for NK₂ binding, a24% inhibition at 1 μM. ##STR95## has a K_(i) for NK₁ binding, of 30 nM;and a K_(i) for NK₂ binding, of 175 nM. ##STR96## has for NK₁ binding, a48% inhibition at 1 μM; and for NK₂ binding, a 0% inhibition at 1 μM.

The K_(i) of a compound is that concentration at which the compoundcaused 50% inhibition of either NK₁ or NK₂. For those compounds of theinvention having higher than 50% inhibition of NK₁, K_(i) 's for NK₁were determined. The K_(i) 's for NK₁ for such compounds fell within arange of about 11 nM to about 176 nM.

For those compounds of the invention having higher than 50% inhibitionof NK₂, K_(i) 's for NK₂ were determined. The K_(i) 's for NK₂ for suchcompounds fell within a range of about 175 nM to about 300 nM.

It will be recognized that compounds of formula I exhibit NK₁ and NK₂antagonist activity to varying degrees, i.e., certain compounds havestrong NK₁ antagonist activity, but weaker NK₂ antagonist activity.Others are strong NK₂ antagonists, but weaker NK₁ antagonists. Whilecompounds with approximate equipotency are preferred, it is also withinthe scope of this invention to use compounds of with unequal NK_(1/) NK₂antagonist activity when clinically appropriate.

Certain compounds of formula I have been found to be antagonists of bothNK₁ and NK₂ receptors, and are therefore useful in treating conditionscaused or aggravated by the activity of NK₁ and NK₂ receptors.

The present invention also relates to a pharmaceutical compositioncomprising a compound of formula I and a pharmaceutically acceptablecarrier. Compounds of this invention can be administered in conventionaloral dosage forms such as capsules, tablets, powders, cachets,suspensions or solutions, or in injectable dosage forms such assolutions, suspensions, or powders for reconstitution. Thepharmaceutical compositions can be prepared with conventional excipientsand additives, using well known formulation techniques. Pharmaceuticallyacceptable excipients and additives include nontoxic and chemicallycompatible fillers, binders, disintegrants, buffers, preservatives,anti-oxidants, lubricants, flavorings, thickeners, coloring agents,emulsifiers and the like.

The daily dose of a compound of formula I for treating asthma, cough,bronchospasm, inflammatory disease, migraine, nociception andgastrointestinal disorders is about 0.1 mg to about 20 mg/kg of bodyweight per day, preferably about 0.5 to about 15 mg/kg, more preferably0.5 to about 5 mg/kg. For an average body weight of 70 kg, the dosagerange is therefore from about 1 to about 1500 mg of drug per day,preferably about 50 to about 100 mg, given in a single dose or 2-4divided doses. The exact dose, however is determined by the attendingclinician, and is dependent on the potency of the compound administered,the age, weight, condition and response of the patient.

The invention disclosed herein is examplified by the following examples,which should not be construed to limit the scope of the disclosure.Alternative mechanistic pathways and analogous structures within thescope of the invention will be apparent to those skilled in the art.

EXAMPLE 1 Preparation of (±)-1-3,5-bis(trifluoromethyl)phenyl!methyl!-3-phenylpiperazine,dihydrochloride salt, quarter hydrate ##STR97##

Chloropyrazine (20.68 gram, 177 mmol) and1,2-bis(diphenylphosphino)ethane!nickel(II) chloride (41.08 gram, 77.8mmol) in dry THF (1.5 liter) were mixed and stirred for 80 minutes in aflask (cooled with a water bath) under nitrogen. A solution ofphenylmagnesium bromide (3M in Et₂ O) (103 ml, 309 mmol) was addedslowly through a dropping funnel into the cooled brick-red slurry atroom temperature under nitrogen over 3.5 hours. After stirring at roomtemperature overnight, TLC showed that the reaction was complete. 3N HCl(100 ml) was added slowly through a dropping funnel under nitrogen andthe mixture was stirred for one hour. The THF layer was separated fromthe aqueous layer. The aqueous layer was adjusted to pH 12 with 6N NaOHand extracted with EtOAc (100 ml, 3×). The organic fractions (THF andEtOAc) were combined and dried over MgSO₄, filtered and concentrated togive a solid. The product was purified by flash chromatography on 300 gof flash grade silica gel in 2.5% EtOAc/CH₂ Cl₂ to give 10.79 gram (69mmol, 39%) of 2-phenylpyrazine, m.p. 69-70 C.; FAB mass M+1!⁺ 157;

Found, C, 76.55; H, 5.22; N, 17.71. Calcd. for C₁₀ H₈ N₂, C, 76.90; H,5.16;. N, 19.93.

To a solution of 2-phenylpyrazine (11.64 gram, 74.53 mmol) in aceticacid (58.2 ml) was added palladium acetate Pd(OAc)₂ (2.33 gram, 9.94mmol). The mixture was hydrogenated at 50 psi for four hours. After thereaction was complete, the catalyst was filtered off and rinsed with asmall portion of acetic acid. The filtrate was concentrated under housevacuum to give a brown-black solid which was suspended in deionizedwater (300 ml) and adjusted to pH 13 with 20% NaOH solution. The productwas extracted from aqueous solution with EtOAc (200 ml, 3×), dried overMgSO₄, filtered and evaporated to dryness to give 2-phenylpiperazine(7.2 gram). An additional 1.6 g of 2-phenylpiperazine was obtained byevaporating the aqueous fraction to a solid and triturating the solidwith CH₂ Cl₂. Total yield of 2-phenylpiperazine was 73%. The crudematerial was crystallized from EtOAc and hexane for characterization,m.p. 86°-88° C.; FAB mass M+1!⁺ 163;

Found, C, 74.04; H, 8.66; N, 17.15. Calcd. for C₁₀ H₁₄ N₂, C, 74.04; H,8.69; N, 17.26.

To a solution of 2-phenylpiperazine (4.0 gram, 24.65 mmol) in dry CH₂Cl₂ (200 ml) at -78° C. under nitrogen was added Et₃ N (5.15 ml, 36.97mmol) followed by the dropwise addition of a CH₂ Cl₂ solution(46.60 ml)of bis(trifluoromethyl)benzyl bromide (4.66 ml, 24.65 mmol). The flaskwas kept at -78° C. then it was gradually warmed to room temperatureovernight. After TLC showed that the reaction was complete, the materialwas washed with brine (150 ml, 2×), dried over MgSO₄, filtered, andevaporated under vacuum to yield a tan solid. The crude product waspurified by flash silica gel chromatography (150 g), eluting with 2.5%MeOH/CH₂ Cl₂ to give (±) 1-3,5-bis(trifluoromethyl)phenyl!methyl!-3-phenyl-piperazine (6.96 gram,17.92 mmol, 72.7%) as an oil. A portion of this oil (0.5 gram, 1.287mmol)) was converted to its hydrochloride salt by dissolving the oil inCH₂ Cl₂ (20 ml) and treating with 2.3M HCl-EtOH (1.3 ml, 2.99 mmol).After stirring at room temperature for 10 minutes, all solvents wereremoved under high vacuum and the residue was dried overnight, m.p.229°-233° C.; FAB mass M+1!⁺ 389;

Found, C, 48.83; H, 4.28; N, 5.87; Cl, 14.77; F, 24.03. Calcd. for C₁₉H₁₈ N₂ F₆.2 HCl.0.25 H₂ O, C, 48.99; H, 4.43; N, 6.01; Cl, 15.22; F,24.47.

EXAMPLE 2 Preparation of (±)-4-3,5-bis(trifluoromethyl)phenyl!methyl!-2-phenyl-1-1-(phenylmethyl)-4-piperidinyl!amino!acetyl!piperazine, trihydrochloridesalt, dihydrate. ##STR98##

To a solution of (±) 1-3,5-bis(trifluoromethyl)phenyl!methyl!-3-phenyl-piperazine (0.76 gram,1.975 mmol) in dry CH₂ Cl₂ (15.2 ml) at -78° C. was added Et₃ N (0.286ml, 2.055 mmol) followed by the dropwise addition of bromoacetyl bromide(0.179 ml, 2.055 mmol). After stirring at -78°0C. for 4 hours, thereaction was diluted with CH₂ Cl₂ (200 ml), washed with brine (100 ml,2×) and dried over MgSO₄. After filtration, the solvent was removed togive a light yellow solid which was used without further purification.FAB mass M+1!⁺ 509.2 (⁷⁹ Br).

The product from the previous reaction (1.067 gram, 2.096 mmol) wasdissolved in dry CH₂ Cl₂ (10.67 ml) and cooled to -78° C. undernitrogen. To this cooled solution were added 4-amino-1-benzylpiperidine(0.44 ml, 2.11 mmol) and diisopropylethylamine (0.402 ml, 2.3 mmol). Thereaction was gradually warmed to room temperature overnight undernitrogen. After completion, CH₂ Cl₂ (300 ml) was added and the organiclayer was washed with brine (100 ml, 2×), dried over MgSO₄ and filtered.The filtrate was evaporated under vacuum to give a crude oil which waspurified by flash chromatography on flash grade silica gel (100 g),eluting with 2.5% NH₃ --MeOH-2.5% EtOH/CH₂ Cl₂ to give a light yellowoil (0.76 g, 1,229 mmol, 59%). A portion of the oil (0.27 gram, 0.436mmol) was converted to its hydrochloride salt by dissolving in CH₂ Cl₂(13.5 ml) and treating with 2.3M HCl-EtOH (0.938 ml, 2.182 mmol). Afterstirring at room temperature for 40 minutes, solvent was evaporated andthe residue was vacuum dried overnight, m.p. 199°-202° C.; FAB massM+1!⁺ 619.5;

Found, C, 51.73; H, 5.98; N, 7.18; Cl, 13.69; F, 14.75. Calcd. for C₃₃H₃₆ N₄ OF₆.3 HCl.2 H₂ O, C, 51.87 H, 5.67; N, 7.33; Cl, 13.92; F, 14.91.

EXAMPLE 3 Preparation of (±)-4-3,5-bis(trifluoromethyl)phenyl!methyl!-1- 2-(4-hydroxy-4-phenyl-1-piperidinyl)acetyl!-2-phenylpiperazine, dihydrochloride salt, 1.5hydrate ##STR99##

By process analogous to that described in Example 2, employing4-hydroxy-4-phenyl-piperidine in place of 4-amino-1-benzylpiperidine thetitle compound was prepared. m.p. 185°-187° C.; FAB mass M+1!⁺ 606.6

Found, C, 54.58; H, 5.44; N, 5.75; Cl, 9.71; F, 16.11. Calcd. for C₃₂H₃₃ O₂ N₃ F₆.2 HCl .1.5 H₂ O, C, 54.47; H, 5.43; N, 5.96; Cl, 10.05; F,16.16.

By process analogous to that described in Example 2, employingappropriate heterocyclic derivatives (Z group), as listed below, inplace of 4-amino-1-benzyl-piperidine, the following compounds wereprepared.

    __________________________________________________________________________     ##STR100##                                                                                               M + 1!                                            Z             salt    m.p. °C.                                                                    FAB mass                                                                             High Res. Mass                              __________________________________________________________________________     ##STR101##   free form                                                                             198-201                                                                            647.4                                               ##STR102##   3 HCl.2 H.sub.2 O                                                                     192-195                                                                            605.5                                               ##STR103##   2 HCl.1.5 H.sub.2 O                                                                   162-165                                                                            604.5                                               ##STR104##   free form                                                                              45-47                                                                             617.3  Cal'd 617.2715 Found 617.2731                ##STR105##   free form                                                                              66-68                                                                             619.3  Cal'd 619.2872 Found 619.2856                ##STR106##   free form                                                                              68-71                                                                             682.3                                              __________________________________________________________________________

EXAMPLE 4 Preparation of (±)-4-3,5-bis(trifluoromethyl)phenyl!methyl!-2-phenyl-N-1-(phenylmethyl)-4-piperidinyl!-1-piperazineethanamine,tetrahydrochloride salt, monohydrate ##STR107##

To a solution of (±)-4-3,5-bis(trifluoromethyl)phenyl!methyl!-2-phenyl-1-1-(phenylmethyl)-4-piperidinyl!amino!acetyl!piperazine (0.48 g, 0.776mmol) in THF (12 ml) was added 10M BH₃.S(CH₃)₂ (0.388 ml, 3.88 mmol).The mixture was heated in an oil bath at 80° C. under nitrogenovernight. After completion, excess BH₃ was decomposed by dropwiseaddition of MeOH to the cooled solution under nitrogen. MeOH wasevaporated and the residue was redissolved in EtOH (14.4 ml). K₂ CO₃(0.235 gram, 1.707 mmol) was added and the mixture was refluxed at 80°C. for five hours. After TLC showed that the reaction was complete, thesolid was filtered off and the filtrate was evaporated under vacuum. Theresidue was redissolved in EtOAc (300 ml), washed with brine (100 ml)and dried over MgSO₄. It was filtered and evaporated under vacuum togive an oil which was purified by flash chromatography on flash gradesilica gel (80 g), eluting with 3% NH₃ -MeOH/CH₂ Cl₂ to give the desiredmaterial as an oil (0.373 gram, 0.615 mmol, 79%). A portion of the oil(0.36 gram) was converted to its hydrochloride salt by dissolving in dryCH₂ Cl₂ (18 ml), followed by the addition of 2.3M HCl-EtOH (1.3 ml).Solvents were removed after stirring at room temperature for 0.5 hourand the residue was vacuum dried, m.p. 238°-241° C.; FAB mass M+1!⁺605.6;

Found, C, 51.96; H, 5.83; N, 7.01; Cl, 14.52; F, 18.21. Calcd. for C₃₃H₃₈ N₄ F₆.4 HCl.H₂ O, C, 51.57; H, 5.77; N, 7.29, Cl, 14.83; F, 18.45.

EXAMPLE 5 Preparation of (±)-1- 2- 4-3,5-bis(trifluoromethyl)phenyl!methyl!-2-phenyl-1-piperazinyl!ethyl!-4-phenyl-4-piperidinol,trihydrochloride salt, monhydrate ##STR108##

By a process analogous to the process described in Examples 3 and 4 thetitle compound was prepared, m.p. 215°-220° C.; FAB mass M+1!⁺ 592.1;

Found, C, 53.17; H, 5.51; N, 5.77; Cl, 14.37; F, 15.62. Calcd. for C₃₂H₃₅ ON₃ F₆.3 HCl.H₂ O, C, 53.45; H, 5.61; N, 5.84; Cl, 14.79; F, 15.85.

By a process analogous to the process described in Examples 3 and 4,employing appropriate heterocyclic derivatives (Z group), listed below,in place of 4-amino-1-benzyl-piperidine, the following compounds wereprepared.

    ______________________________________                                         ##STR109##                                                                                                       M + 1!.sup.+                              Z           salt          m.p. °C.                                                                        FAB mass                                   ______________________________________                                         ##STR110## 4 HCl.1.0 H.sub.2 O                                                                         >230     591.1                                       ##STR111## 3 HCl.1.0 H.sub.2 O                                                                         >260     590.9                                      ______________________________________                                    

EXAMPLE 6 Preparation of (±)-N- 1- 2- 4-3,4-bis(trifluoromethyl)phenyl!methyl!-2-phenyl-1-piperazinyl!ethyl!-4-phenyl-4-piperidinyl!acetamide,trihydrochloride salt, 1.5 hydrate ##STR112##

To a solution of the product from Example 5 (free form) (0.66 gram,1.116 mmol) in 5.0 ml of acetonitrile was added dropwise concentratedsulfuric acid (2.44 ml) at room temperature under nitrogen. After 4hours, water (100 ml) was added to the reaction and the solution wasadjusted to pH 9 with 10% NaOH solution. The product was extracted fromthe aqueous solution with EtOAc (100 ml, 3×). The organic fractions werecombined and washed with brine (100 ml), dried over MgSO₄, filtered, andconcentrated under vacuum to give an oil. The product was purified byflash chromatography on flash silica gel (80 g) and was eluted with 10%NH₃ --MeOH/CH₂ Cl₂ to give an oil (0.40 g, 0.774 mmol, 69%). A portionof this oil (0.4 g, 0.632 mmol) was dissolved in CH₂ Cl₂ (20 ml) andtreated with 2.3M HCl-EtOH (2.528 mmol). After stirring at RT for 0.5hour, solvents were removed under vacuum to give a white solid, m.p.245°-247° C.; FAB mass M+1!⁺ 633.4;

Found, C, 53.27; H, 5.80; N, 7.23; Cl, 13.91; F, 14.55. Calcd. for C₃₄H₃₈ ON₄ F₆.3 HCl.1.5 H₂ O, C, 53.09; H, 5.76; N, 7.28; Cl, 13.83; F,14.82.

EXAMPLE 7 Preparation of (±)-1-(2-methoxyphenyl)methyl!-3-phenyl-piperazine, dihydrochloride salt,monohydrate ##STR113##

To a solution of 1-hydroxymethyl-2-methoxybenzene (28.7 gram, 0.207 mol)in CH₂ Cl₂ (574 ml) at 0° C. under nitrogen was added slowly PBr₃ (13.66ml, 0.145 mol). After stirring for an additional 1.5 hours, MeOH (13.66ml) was added and stirred for 5 minutes. To this mixture was addeddropwise 10% Na₂ CO₃ (2 ml) solution and stirred for 5 minutes. Themixture was then washed with 10% Na₂ CO₃ (50 ml, 2×) and brine (100 ml).It was dried over MgSO₄, and filtered. The filtrate was removed undervacuum to give an oil (40 gram) of 1-bromomethyl-2-methoxy-benzene. Thismaterial was used without purification.

To a solution of (±)-2-phenyl-piperazine (2.83 gram, 17.44 mmol)(described in Example 1) in dry CH₂ Cl₂ (141.5 ml) at -78° C. was addedslowly a solution of 1-bromomethyl-2-methoxy-benzene (3.507 gram, 17.44mmol) in dry CH₂ Cl₂ (35 ml) under nitrogen. The reaction was stirred at-78° C. and gradually warmed to RT overnight. After completion, theproduct was diluted with CH₂ Cl₂ (200 ml), washed with brine (100 ml),dried over MgSO₄ and filtered. The filtrate was removed under vacuum togive an oil. The product was purified by flash chromatography on flashgrade silica gel (150 g), eluting with 4% MeOH/CH₂ Cl₂ to give the titlecompound as an oil (2.68 gram, 54%). A portion of this oil (0.33 gram,1.168 mmol) was dissolved in CH₂ Cl₂ (10.0 ml) and treated with 2.3M HCl(1.1 ml, 2.53 mol). After stirring at room temperature for 10 minutes,solvents were removed under vacuum to give a solid, m.p. 152°-156° C.;FAB mass M+1!⁺ 283.2.

Found, C, 58.18; H, 7.23; N, 7.33; Cl, 18.89. Calcd. for C₁₈ H₂₂ON₂.2HCl.H₂ O, C, 57.91; H, 7.02; N, 7.50; Cl, 18.99.

EXAMPLE 8 Preparation of (±)-1-(4-hydroxy-4-phenyl-1-piperidinyl)acetyl!-4-(2-methoxy-phenyl)methyl!-2-phenyl piperazine, dihydrochloride salt##STR114##

The bromoacetyl derivative of the product from Example 7 was preparedaccording to the procedure described in Example 2. This intermediate wasused for the next reaction without further purification. The titlecompound was prepared by employing a process analogous to that describedin Example 3, via the bromoacetyl derivative of (±)-1-(2-methoxyphenyl)methyl!-3-phenyl-piperazine to give a solid, m.p.183°-186° C.; FAB mass M+1!⁺ 500;

Found, C, 61.30; H, 7.54; N, 6.98; Cl, 11.65. Calcd. for C₃₁ H₃₇ N₃O₃.2HCl, C, 61.18; H, 7.12; N, 6.90; Cl, 11.65.

EXAMPLE 9 Preparation of (±)-1- 2- 4-(2-methoxyphenyl)methyl!-2-phenyl-1-piperazinyl!ethyl!-4-phenyl-4-piperidinol##STR115##

The product from Example 8 (free form) (0.7 gram, 1.4 mmol) was used toprepare the title compound by employing a procedure analogous to theprocedure for Example 4. The title compound was a solid, m.p. 63°-65°C.; FAB mass M+1!⁺ 486;

Found, C, 75.86; H, 8.52; N, 8.54. Calcd. for C₃₁ H₃₉ N₃ O₂, C, 75.54;H, 8.14; N, 8.53.

EXAMPLE 10 Preparation of 4-3,5-bis(trifluoromethyl)phenyl!methyl!-α-methyl-2-phenyl-1-piperazineacetamide,dihydrochloride salt, monohydrate (diastereomeric mixture) ##STR116##

A mixture containing (±)-1-3,5-bis(trifluoromethyl)-phenyl!-methyl!-3-phenyl piperazine (Example 1,free form) (0.5 gram, 1.3 mmol), 2-bromopropionamide (0.213 gram, 1.4mmol), K₂ CO₃ (0.193 gram, 1.4 mmol), n-Bu₄ NHSO₄ (0.44 gram, 1.3 mmol),and dry DMF (20ml) was heated at 80° C. overnight under nitrogen. Afterthe reaction was complete, DMF was removed under vacuum and the residuewas redissolved in EtOAc, washed with brine, dried over MgSO₄, andfiltered. The filtrate was concentrated under vacuum to give a brown oil(0.55 g). The product was purified by flash chromatography on flashgrade silica gel (70 g), and eluted with 3% MeOH/CH₂ Cl₂ to give an oil(0.32 g, 53%). A portion of this oil (0.14 g, 0.305 mmol) was dissolvedin CH₂ Cl₂ (5 ml) and treated with 2.35M HCl/MeOH (0.324 ml, 0.762mmol). After stirring at RT for 10 minutes, solvents were evaporatedunder vacuum to give a solid, m.p.>175° C., no sharp melting point; FABmass M+1!⁺ 460.8;

Found, C, 48.09; H, 4.73; N, 7.50; Cl, 12.43; F, 20.93. Calcd. for C₂₂H₂₃ N₃ OF₆.2HCl.H₂ O C, 48.01; H, 4.94; N, 7.63; Cl, 12.88; F, 20.71.

EXAMPLE 11 Preparation of (±)-1-acetyl-4-3,5-bis(trifluoromethyl)phenyl!methyl!-2-phenylpiperazine, hydrochloride##STR117##

To a solution of (±)-1 -3,5-bis(trifluoromethyl)phenyl!-methyl!-3-phenyl-piperazine (0.4 gram,1.03 mmol) in dry CH₂ Cl₂ (5 ml) was added diisopropyl ethyl amine (0.15g, 1.1 mmol) and acetyl chloride (0.081 g, 1.03 mmol). The solution wasstirred at 0° C. and warmed to RT overnight under nitrogen. After thereaction was complete, the product was diluted with EtOAc (100 ml) andwashed with brine (20ml, 3×). It was dried over MgSO₄, filtered andconcentrated to give an oil (0.35 g, 0.81 mmol, 79%). The oil wasconverted to its hydrochloride salt as described in Example 10 to give awhite solid, m.p. 202°-203 ° C.; FAB mass M+1!⁺ 431;

Found, C, 53.76; H, 4.51; N, 6.00; Cl, 7.48; F, 24.54. Calcd. for C₂₁H₂₀ N₂ OF₆.HCl, C, 54.02; H, 4.53; N, 6.00; Cl, 7.60; F, 24.42

EXAMPLE 12 Preparation of (±)-1-3,5-bis(trifluoromethyl)phenyl!methyl!-3-(3,4-dichlorophenyl)-piperazine,dihydrochloride salt ##STR118##

To a solution of ethylene diamine (30.0 gram, 0.5 mol) in MeOH (300 ml)at -10° C. under nitrogen was added dropwise a solution ofdi-t-butyldicarbonate (22 g, 0.1 mol) in MeOH (250 ml). The reaction wasstirred at -10° C. for 5 hours then gradually warmed to RT overnight.After the reaction was complete, the mixture was concentrated undervacuum to give a residue which was suspended in CH₂ Cl₂ (500 ml) andwashed with brine (200 ml, 2×). The organic fraction was dried overMgSO₄, filtered and concentrated under vacuum to give an oil (10.8 g)which contained 10% of di-t-BOC protected material.

To a solution of the product (9.0 gram, 56 mmol) from the previousreaction in CH₂ Cl₂ (50 ml) was added slowly3,5-bis(trifluoromethyl)-benzaldehyde (15 g, 62 mmol) at 0° C. undernitrogen. To this mixture was added Na₂ SO₄ (4 g) and it was stirredovernight at RT. Na₂ SO₄ was filtered off and CH₂ Cl₂ was removed togive a clear oil which was redissolved in absolute EtOH (100 ml). Tothis solution was added NaBH₃ CN (5.3 g, 84 mmol) and acetic acid (20ml). The mixture was stirred overnight under nitrogen. After thereaction was complete, the mixture was concentrated under vacuum to givea residue which was redissolved in EtOAc and brine, basified to pH 8.The product was extracted from the aqueous solution with EtOAc (100 ml,2×) and washed with brine (100 ml, 2×). The EtOAc fractions werecombined and dried over MgSO₄, filtered and concentrated to give an oil(20 g). The product was purified by flash chromatography on flash gradesilica gel (500 g) and eluted with 2.5% MeOH/CH₂ Cl₂ to yield 17.3 g(44.78 mmol, 80%) of N-t-BOC-N'-3,5-bis(trifluoromethyl)phenyl ethylenediamine. FAB mass M+1!⁺ 387.2.

A mixture of the above product (10.5 g, 272 mmol), 3,4-dichlorophenacylbromide (7.3 g, 272 mmol) and diisopropylethylamine (3.9 g, 30 mmol) indry THF (50 ml) was stirred at RT under nitrogen overnight. After thereaction was complete, the white solid was filtered off and the filtratewas concentrated under vacuum to give a residue which was trituratedwith ether and the solid was filtered off. The ether solution wasconcentrated to give a crude brown oil (16 g) which was used for thenext reaction without purification. FAB mass M+1!⁺ 573.575

To a solution of the above product (16 g, 27.9 mmol) in CH₂ Cl₂ (10 ml)was added trifluoroacetic acid (18 ml) and the mixture was stirred at RTfor 3 hours under nitrogen. The excess TFA and solvent were removedunder vacuum and the resulting brown oil was redissolved in MeOH (50 ml)and removed again under vacuum to give a brown solid. The brown solidwas suspended in MeOH (100 ml) and NaBH₃ CN (3.5 g, 55.8 mmol) was addedportionwise. After stirring at RT overnight, the solvent was removed. Tothe residue was added CH₂ Cl₂ (200 ml) and brine (200 ml), then basifiedwith 3N NaOH to pH 10. The product was extracted from the aqueoussolution with CH₂ Cl₂ (100 ml, 2×), dried over MgSO₄, filtered, and thefiltrate was concentrated under vacuum to give a light brown oil (12.5g). The product was purified by flash chromatography on flash gradesilica gel (300 g) and eluted with 2% MeOH/CH₂ Cl₂ to give a light brownoil (10.5 g, 22.97 mmol, 83%).

A portion of this oil (0.2 g, 0.435 mmol) was dissolved in MeOH (92 ml)and treated with 2.35M HCl/MeOH (0.4 ml, 0.94 mmol). After stirring for10 minutes at RT, the solvent was removed and dried under vacuum to givethe title compound as a white solid (0.25 g), m.p. 234°-236° C.; FABmass M+1!⁺ 457.459;

Found, C, 42.67; H, 3.40; N, 5.29; Cl, 26.70; F, 21.38. Calcd. for C₁₉H₁₆ N₂ Cl₂ F₆.2 HCl, C,43.04; H, 3.42; N, 5.28; Cl, 26.75; F, 21.50.

EXAMPLE 13 Preparation of (±)-4-3,5-bis(trifluoromethyl)phenyl!methyl!-2-(3,4-dichlorophenyl)-1-1-(phenylmethyl)-4-piperidinyl!amino!acetyl!-piperazine. ##STR119##

By a procedure analogous to the procedure described in the first part ofExample 2, using (±)-1-3,5-bis(trifluoromethyl)phenyl!-methyl!-3-(3,4-dichlorophenyl)-piperazinein place of (±)-1-3,5-bis-(trifluoromethyl)-phenyl!methyl!-3-phenyl-piperazine, thebromoacetyl derivative was obtained in 78% from its starting material asa solid, m.p. 146°-148° C.; FAB mass M+1!⁺³⁵ Cl 577. 579.

By a procedure analogous to the procedure described in the second partof Example 2, the title compound was obtained as a solid (48%) afterpurification by flash chromatography on flash grade silica gel (70 g),eluting with 4% MeOH/CH₂ Cl₂, m.p. 53°-55° C.; FAB mass M+1!⁺³⁵ Cl 687;

Found, C, 56.98; H, 4.72; N, 8.13; Cl, 10.67; F, 16.30. Calcd. for C₃₃H₃₄ N₄ Cl₂ F₆ O.0.25 H₂ O, C, 57.27; H, 5.03; N, 8.10; Cl, 10.25; F,16.47.

By a procedure analogous to the procedure described in Example 2, butusing (±)-1-3,5-bis(trifluoromethyl)phenyl!methyl!-3-(3,4-dichlorophenyl)-piperazinein place of (±)-1-3,5-bis(trifluoromethyl)phenyl!methyl!-3-phenyl-piperazine, andemploying appropriate heterocyclic derivatives (Z group), listed below,in place of 4-amino-1-benzylpiperidine, the following compounds wereprepared.

EXAMPLE 14

    __________________________________________________________________________     ##STR120##                                                                                            M + 1!.sup.+                                                                 FAB mass                                                                              M + 1!.sup.+                                  Z                  m.p °C.                                                                     based on .sup.35 Cl                                                                  High Res. Mass                                 __________________________________________________________________________     ##STR121##   free form                                                                          108-110     Cal'd 715.2041 Found 715.2050                   ##STR122##   2 H.sub.2 O                                                                        58-60       Cal'd 673.1936 Found 673.1935                   ##STR123##   free form                                                                          55-57                                                                              672                                                    ##STR124##   0.25 H.sub.2 O                                                                     55-57                                                                              685                                                    ##STR125##   free form                                                                          74-76                                                                              687                                                    ##STR126##   free form                                                                          82-83                                                                              750                                                    ##STR127##   free form                                                                          105-107                                                                            702                                                    ##STR128##   free form                                                                          85-86                                                                              674                                                   __________________________________________________________________________

EXAMPLE 15 Preparation of (±)-1- 2- 4-3,5-bis(trifluoromethyl)phenyl!methyl!-2-(3,4-dichlorophenyl)-1-piperazinyl!ethyl!-4-phenyl-4-piperidinol ##STR129##

By a procedure analogous to the procedure described in Example 4, usingthe last compound from Example 14, as a starting material, the titlecompound was prepared in 67% yield as a solid, m.p. 71°-72° C.; FAB massM+1!⁺³⁵ Cl 660;

Found, C, 58.08; H, 5.14; N, 6.40; F, 17.37. Calcd. for C₃₂ H₃₃ N₃ Cl₂F₆ O, C, 58.19; H, 5.04; N, 6.36; F, 17.26.

EXAMPLE 16 Preparation of (±)-4-3,5-bis(trifluoromethyl)phenyl!acetyl!-2-phenyl-1-1-(phenylmethyl)-4-piperidinyl!amino!acetyl!piperazine ##STR130##

To cooled CH₂ Cl₂ (127ml) containing 2-phenylpiperazine (Example 1, 1.0gram, 6.164 mmol), 3,5-bis(trifluoromethyl)phenylacetic acid (1.797 g,6.472 mmol), and N-hydroxybenzotriazole monohydrate (0.874 g, 6.472mmol) at -20° C. were added Et₃ N (0.9ml, 6.472 mmol) andN,N-dimethylaminopropylethylcarbodimide (DEC) under nitrogen. Thereaction was kept at -20° C. for an hour and gradually warmed to RTovernight. After stirring 20 hours, the reaction was complete and CH₂Cl₂ (200 ml) was added. The organic solution was washed with 5% NaHCO₃(100 ml) and brine (100 ml, 3×), dried over MgSO₄, filtered andconcentrated under vacuum to give 2.5 g of crude product. The productwas purified by flash chromatography on flash grade silica gel (120 g),eluting with 3% NH₃ --MeOH/CH₂ Cl₂ to give a gummy solid (2.08 g, 4.996mmol, 81%). A portion of this solid (1.0 g) was crystallized from hexaneand characterized to yield a solid, m.p. 80°-82° C.; FAB mass M+1!⁺417.2;

Calcd. for C₂₀ H₁₈ ON₂ F₆, C, 57.69; H, 4.36; N, 6.73; F, 27.38.

Found, C, 57.91; H, 4.55; N, 6.69; F, 27.61.

To a solution of the above compound (1.1 1 g, 2.642 mmol) in dry CH₂ Cl₂(22.2 ml) at -78° C. was added diisopropylethylamine (0.483 ml, 2.774mmol) followed by the dropwise addition of bromoacetyl bromide (0.246ml, 2.774 mmol). After stirring at -78° C. for 7 hours under nitrogen,additional diisopropylethylamine (0.51 ml, 2.9 mmol) and4-amino-1-benzylpiperidine (0.605 ml, 2.9 mmol) were added at -78° C.The reaction was gradually warmed to RT overnight. After the reactionwas complete, the reaction was diluted with CH₂ Cl₂ (150 ml), washedwith brine (50 ml, 3×) and dried over MgSO₄. After filtration, thesolvent was removed under vacuum to give a light yellow solid which waspurified by flash chromatography on flash grade silica gel (150 g),eluting with 5% NH₃ --MeOH/CH₂ Cl₂ to give the title compound as a whitesolid (0.94, g, 1.453 mmol, 55%), m.p. 49°-52° C.; FAB mass M+1!⁺ 647.3;

Calcd. for C₃₄ H₃₆ O₂ N₄ F₆, C, 63.15; H, 5.16; N, 8.66; F, 17.62.Found, C, 62.73; H, 5.77; N, 8.56; F, 17.68.

EXAMPLE 17 Preparation of (±)-4- 2-3,5-bis(trifluoromethyl)phenyl!ethyl!-2-phenyl-N-1-(phenylmethyl)-4-piperidinyl!-1-piperazineethanamine, fourhydrochloride salt, hemihydrate ##STR131##

To a solution of the product from Example 16 (0.463 gram, 0.72 mmol) indry THF (21.6 ml) was added a 10M solution of BH₃.S(CH₃)₂ (0.716 ml,7.16 mmol) at RT under nitrogen. The solution was heated at 80° C. undernitrogen for 24 hours. After cooling to RT, MeOH (5 ml) was added slowlyto decompose excess BH₃. S(CH₃)₂. All solvents were removed under vacuumand the residue was redissolved in absolute EtOH (14.1 ml), followed bythe addition of K₂ CO₃ (0.22 g, 1.58 mmol). The mixture was heated at80° C. for 6.5 hours under nitrogen. After cooling K₂ CO₃ was filteredand EtOH was removed to give a residue which was redissolved in EtOAc(150 ml) and washed with brine (50 ml, 2×). It was dried over MgSO₄,filtered, and evaporated under vacuum to give a solid (0.42 g) which waspurified by flash chromatography on flash grade silica gel (80 g),eluting with 4% NH₃ --MeOH/CH₂ Cl₂ to give a white solid (0.14 g, 0.227mmol, 49%).

The above material (0.14 g, 0.227 mmol) was treated with CH₂ Cl₂ (6.8ml) and 2.3M HCl-EtOH (0.592 ml, 1.362 mmol). After stirring at RT for10 minutes, the solution was evaporated under high vacuum to give awhite solid, m.p. 182°-190° C.; High Res. MS M+1!⁺ ; Calcd. for C₃₄ H₄₁N₄ F₆, 619.3235, Found, 619.3222.

Calcd. for C₃₄ H₄₀ N₄ F₆.4 HCl.0.5 H₂ O, C, 52.79; H, 5.86; N, 7.24, F,14.73; Cl, 18.33. Found, C, 52.58; H, 6.10; N, 7.21; F, 14.77; Cl,16.71.

EXAMPLE 18 Preparation of (±)-2-phenyl-1-(1-phenylmethyl)-4-piperidinyl!amino!acetyl!-4-(3,4,5-trimethoxylphenyl)acetyl!piperazine, hemihydrate ##STR132##

By a procedure analogous to the procedure described in Example 16, using3,4,5-trimethoxyphenylacetic acid in place of3,5-bis(trifluoromethyl)phenylacetic acid, the title compound wasprepared as a solid, m.p. 53°-56° C., High Res. MS: M+1!⁺ Calcd. for C₃₅H₄₅ N₄ O₅ 601.3390; Found, 601.3393.

Calcd. for C₃₅ H₄₄ N₄ O₅.0.5 H₂ O, C, 68.94; H, 7.43; N, 9.19. Found, C,69.21; H, 7.53; N, 9.22.

EXAMPLE 19 Preparation of (±)-2-phenyl-N-1-(phenylmethyl)-4-piperidinyl!-4-2-(3,4,5-trimethoxyphenyl)ethyl!-1-piperazineethanamine, fourhydrochloride salt, monohydrate ##STR133##

By essentially the same process as described in Example 17, using theproduct from Example 18 in place of the product from Example 16, thetitle compound was prepared as a solid, m.p. 167° C. (wet, no sharpmelting point); High Res. MS: M+1!⁺ Calcd. for C₃₅ H₄₉ N₄ O₃, 573.3805,Found, 573.3810.

Calcd. for C₃₅ H₄₈ N₄ O₃. 4HCl . H₂ O, C, 57.07; H, 7.39; N, 7.61; Cl,19.25. Found, C, 57.16; H, 7.88; N, 7.64, Cl, 18.71.

EXAMPLE 20 Preparation of (±)-4- 2-3,5-bis(trifluoromethyl)phenyl)ethyl!-2-phenyl-1-1-(phenylmethyl)-4-piperidinyl!amino!acetyl!piperazine, trihydrochloridesalt ##STR134##

By a process analogous to the reduction process described in the firstpart of Example 17, using (±)-3,5-bis-(trifluoromethyl)phenyl!acetyl!-3-phenylpiperazine (described inthe first part of Ex. 16) as a starting material, (±)-4- 2-bis(trifluoromethyl)-phenyl!ethyl!-2-phenyl piperazine was prepared as asolid after purification by flash chromatography, m.p. 193°-195° C., FABmass M+1!⁺ 403.3. This material (0.38 g, 0.94 mmol) was converted to itsbromoacetylderivative according to the same procedure as described inthe second step of Example 16. After reaction was complete, the materialwas alkylated with 4-amino-1-benzylpiperidine without isolation, usingthe same procedure as described in the third step of Example 16. Thetitle compound was obtained as a solid by flash chromatography, thenconverted to its HCl salt by treatment with HCl/MeOH solution. m.p.214°-216° C., High Res. MS: M+1!⁺ Calcd. for C₃₄ H₃₉ N₄ OF₆, 633.3028;Found, 633.3034.

EXAMPLE 21 Preparation of (±)-2-phenyl-1-(1-phenylmethyl)-4-piperidinyl!amino!acetyl!-4-2-(3,4,5-trimethoxyphenyl)ethyl!piperazine ##STR135##

By a reduction process analogous to that described in the first part ofExample 17, using (±)-3-phenyl-1-(3.4.5-trimethoxyphenyl)acetyl!piperazine as a starting material(described in the first part of Example 18) (±)-2-phenyl-4-2-(3,4,5-trimethoxy)phenyl!-ethyl!-piperazine was prepared as a solidafter purification by flash chromatography, m.p. 160°-16° C., FAB massM+1!⁺ 357.4. This material (0.53 g, 1.48 mmol) was converted to itsbromoacetyl derivative according to the same procedure as described inthe second step of Example 16. After reaction is complete, thebromoacetyl derivative is alkylated in situ with4-amino-1-benzylpiperidine, using the same procedure as described in thethird step of Example 16.

The title compound can be obtained and purified by flash chromatography.

EXAMPLE 22 Preparation of (±)-4-3,5-bis(trifluoromethyl)phenyl!methyl!-6-(3,4-dichloro-phenyl)-1- 2-1-(phenylmethyl)-4-piperidinyl!amino!ethyl!2-piperazinone ##STR136##

A mixture of glycine ethylester hydrochloride salt (2.9 gram, 20.6mmol), 3,5-bis(trifluoromethyl)benzaldehyde (5.0 g, 20.6 mmol) andtriethyl amine (2.1 g, 20.6 mmol) in MeOH (70 ml) was stirred at RT for40 minutes under nitrogen. To the above solution was added acetic acid(20 ml) and NaBH₃ CN (2.6 g, 41.2 mmol). After stirring at RT for 4days, half of the solvent was removed and AcOH (10 ml) was added thenstirred at RT for an additional two days. All solvent was removed togive a white paste which was mixed with CH₂ Cl₂ (100 ml) and brine (50ml), and basified with 3N NaOH to about pH 10. The product was extractedfrom the aqueous solution with CH₂ Cl₂, dried over MgSO₄, filtered andevaporated to give an oil (7.5 g). The product was purifed by flashchromatography on flash grade silica gel (170 g), eluting with 20%EtOAc/Hexane to give compound (1) (2.7 g) FAB mass M+1!⁺ 330.

Compound(1) (4.92 g, 14.76 mmol), obtained from a large scalepreparation, was dissolved in THF (80 ml) and treated with Hunig's base(1.89 g, 14.76 mmol) and 3,4-dichlorophenacyl bromide (4.35 g, 16.4mmol). The solution was stirred at RT under nitrogen for 3 days. Afterreaction was complete, THF was removed under vacuum and the residue wasdissolved in CH₂ Cl₂ -ether (800 ml), washed with brine (200 ml, 3×),dried over Na₂ SO₄, filtered and evaporated under vacuum to give a browngum. Product was purified by flash chromatography to give compound (2)as a light paste, FAB mass M+1!⁺ 35 Cl, 516. ##STR137##

A mixture of compound (2) and 1.2 equivalents of NH₄ OAc is heated atappropriate temperature to form compound (3). The compound (3) istreated with NaH/DMF and alkylates with 2-bromomethyl-1,3-dioxolane togive compound (4). After removal the protecting group of compound (4)with HCl/dioxane, the desired compound (5) is obtained by reductiveamination (NaBH₃ CN/MeOH) with 4-amino-1-benzyl-piperidine.

The following compounds can be prepared by employing essentially thesame processes covered from Example 1 to Example 22 with appropriatestarting materials and reagents, as described above.

EXAMPLES OF COMPOUND 22

    ______________________________________                                         ##STR138##                                                                   X                Y                                                            ______________________________________                                         ##STR139##                                                                    ##STR140##                                                                    ##STR141##                                                                    ##STR142##                                                                    ##STR143##                                                                   ______________________________________                                    

EXAMPLES OF COMPOUND 22C

    ______________________________________                                         ##STR144##                                                                   X                Y                                                            ______________________________________                                         ##STR145##                                                                    ##STR146##                                                                    ##STR147##                                                                    ##STR148##                                                                    ##STR149##                                                                    ##STR150##                                                                    ##STR151##                                                                    ##STR152##                                                                    ##STR153##                                                                    ##STR154##                                                                    ##STR155##                                                                    ##STR156##                                                                   ______________________________________                                    

EXAMPLE 23

The following compounds can be prepared by employing processes analogousto those set forth in Examples 1 to Example 22 using appropriatestarting materials and reagents, as described above. Those compoundsjust below, which have been given without any physical data, have notbeen made. Those compounds just below which have melting points, havebeen made.

EXAMPLE 23

    ______________________________________                                         ##STR157##                                                                   A                 Z                                                           ______________________________________                                         ##STR158##                                                                    ##STR159##                                                                    ##STR160##                                                                    ##STR161##                                                                    ##STR162##                                                                    ##STR163##                                                                    ##STR164##                                                                    ##STR165##                                                                    ##STR166##                                                                    ##STR167##                                                                   ______________________________________                                    

EXAMPLE 24 Preparation of (±)-1 -3,5-bis(trifluoromethyl)phenyl!methyl!-5-(3,4-dichlorophenyl)-4-1-(phenylmethyl)-4-piperidylamino!acetyl!2-piperazinone ##STR168##

To a solution of 3,4-dichloro-1-(1-hydroxy-2-nitro)ethylbenzene (6.2 g,27.92 mmol) in THF(100 ml) at 0° C. was added slowly a DME solution of0.5M LiAlH₄ (200 ml, 100 mmol) under argon. The ice-water bath wasremoved after the addition of LAH. After stirring at RT for 5 hours, thereaction was slowly quenched with dropwise addition of saturated Na₂ SO₄solution (45 ml) under argon. It was stirred at RT for one hour andprecipate was filtered. The filtrate was concentrated under vacuum togive a light brown oil. The product (2) was purified by flashchromatography on flash grade silica gel (200 g) and eluting with 2.5%NH₃ --MeOH--CH₂ Cl₂. FAB mass for C₈ H₉ ONCl₂ M+1!⁺ 35 Cl, 206.

To a solution of the above product (2) (2.1 g, 10.19 mmol) in THF (210ml) was added N-t-butoxycarbonyl glycine (1.91 g, 10.69 mmol) andN-hydroxybenzotriazole monohydrate (1.44 g, 10.69 mmol). The solutionwas cooled to -20° C. under nitrogen. To the cooled solution was addedEt₃ N (1.49 ml, 10.69 mmol) and N,N-dimethylaminopropylethylcarbodiimide(2.05 g, 10.69 mmol). The mixture was stirred at -20° C. for an hourthen gradually warmed to RT overnight. After the reaction was complete,the reaction was diluted with CH₂ Cl₂ (200 ml), washed with brine (150ml, 3×), dried over MgSO₄, filtered and evaporated under vacuum. Thecrude product (3) was used without further purification. FAB Mass M+1!⁺for ³⁵ Cl, 363.2.

Compound (3) was oxidized to the keto derivative (4) by PCC/CH₂ Cl₂ atRT, FAB Mass M+1!⁺ for ³⁵ Cl, 361.1. Compound (4) was cyclized tocompound (5) via in-situ reductive amination with NaBH₃ CN in MeOH afterremoval of t-BOC protecting group. Compound (5) was protected with t-BOCanhydride in CH₂ Cl₂ to give compound (6). ##STR169##

Compound (6) is treated with NaH/DMF and3,5-bis(trifluoromethyl)benzylbromide to yield compound (7). Afterremoval of t-BOC protecting group of (7), followed by acetylation withbromoacetylbromide, compound (8) is obtained. Alkylation of (8) with4-amino-1-benzylpiperidine gives compound (9).

The following compounds are prepared by employing analogous processescovered from Example 1 to Example 24 with appropriate materials andreagents, as described above.

EXAMPLES OF COMPOUND 24A

    ______________________________________                                         ##STR170##                                                                   X                Y                                                            ______________________________________                                         ##STR171##                                                                    ##STR172##                                                                    ##STR173##                                                                    ##STR174##                                                                    ##STR175##                                                                   ______________________________________                                    

EXAMPLES OF COMPOUND 24 C

    ______________________________________                                         ##STR176##                                                                   X                Y                                                            ______________________________________                                         ##STR177##                                                                    ##STR178##                                                                    ##STR179##                                                                    ##STR180##                                                                    ##STR181##                                                                    ##STR182##                                                                    ##STR183##                                                                    ##STR184##                                                                    ##STR185##                                                                    ##STR186##                                                                    ##STR187##                                                                    ##STR188##                                                                   ______________________________________                                    

EXAMPLE 25 Preparation of (±)-1 -3,5-bis(trifluoromethyl)phenyl!methyl!-5-(3,4-dichlorophenyl)-4- 2-1-(phenylmethyl)-4-piperidinyl!amino!ethyl!2-piperazone

General Method of Synthesis Example 25 ##STR189##

Using the intermediate 6 prepared in the example 24 as a startingmaterial, compound 2 is obtained by removal the t-BOC protecting groupwith CF₃ COOH. Treatment of 2 with Cs₂ CO₃ /DMF then alkylation with2-bromomethyl-1,3-dioxolane gives compound 3. Follow by removal theprotecting group of 3 and in-situ reductive amination with4-amino-1-benzylpiperidine in the presence of NaBH₃ CN/MeOH, compound 4is obtained.

The following compounds can be prepared by employing processes analogousto those set forth in Example 1 to Example 25 using appropriatematerials and reagents, as described above.

EXAMPLES OF COMPOUND 25A

    ______________________________________                                         ##STR190##                                                                   X                Y                                                            ______________________________________                                         ##STR191##                                                                    ##STR192##                                                                    ##STR193##                                                                    ##STR194##                                                                    ##STR195##                                                                   ______________________________________                                    

EXAMPLES OF COMPOUND 25C

    ______________________________________                                         ##STR196##                                                                   X                Y                                                            ______________________________________                                         ##STR197##                                                                    ##STR198##                                                                    ##STR199##                                                                    ##STR200##                                                                    ##STR201##                                                                    ##STR202##                                                                    ##STR203##                                                                    ##STR204##                                                                    ##STR205##                                                                    ##STR206##                                                                    ##STR207##                                                                    ##STR208##                                                                   ______________________________________                                    

What is claimed is:
 1. A compound of the formula: ##STR209## whereineach R₁ is independently ##STR210## and where R_(a) is not H in##STR211## and each R₂, and R₃ is independently ##STR212## each R_(a)and R_(b) is independently selected from the group consisting of H, C₁-C₆ alkyl, CF₃, C₂ F₅, phenyl, and benzyl;each R_(c) and R_(c') isselected from the group consisting of H, C₁ -C₆ alkyl, C₂ -C₆ alkenyl,C₂ -C₆ alkynyl, unsubstituted or substituted phenyl, and unsubstitutedor substituted benzyl, with the proviso that no more than one R_(c) isother than H in the ##STR213## moiety, and no more than one R_(c') isother than H in the ##STR214## moiety; ##STR215## n is 0 to 5; l₃ is 2,x is 0, and y is 2 to 4; or x is 1, and y is 0 to 3; Z is ##STR216## m₂is 0 to 2; n₂ is 1 to 2; each t is 0 to 4; each u is independently 0 to2; and R₉ is selected from the group consisting of ##STR217## whereinR_(a) is not H, when R₉ is ##STR218## and wherein substituted means 1 to3 substituents independently selected from the group consisting of H, C₁-C₆ alkyl, CF₃, C₂ F₅, OH, OC₁ -C₆ alkyl, Cl, Br, I and F; or apharmaceutically acceptable salt thereof.
 2. A compound of the formula:##STR219## wherein each R₁ is independently ##STR220## and where R_(a)is not H in ##STR221## and each R₂, and R₃ is independently ##STR222##each R_(a) and R_(b) is independently selected from the group consistingof H, C₁ -C₆ alkyl, CF₃, C₂ F₅, phenyl, and benzyl;each R_(c) and R_(c')is selected from the group consisting of H, C₁ -C₆ alkyl, C₂ -C₆alkenyl, C₂ -C₆ alkynyl, unsubstituted or substituted phenyl, andunsubstituted or substituted benzyl, with the proviso that no more thanone R_(c) is other than H in the ##STR223## moiety, and no more than oneR_(c') is other than H in the ##STR224## moiety; R₄ is ##STR225## n is 0to 5; 13 is 2, x is 0, and y is 2 to 4; or x is 1, and y is 0 to 3; Z is##STR226## m₂ is 0 to 2; n₂ is 1 to 2; each t is 0 to 4; each u isindependently 0 to 2; and R₉ is selected from the group consisting of##STR227## wherein R_(a) is not H, when R₉ is ##STR228## and whereinsubstituted means 1 to 3 substituents independently selected from thegroup consisting of H, C₁ -C₆ alkyl, CF₃, C₂ F₅, OH, OC₁ -C₆ alkyl, Cl,Br, I and F; or a pharmaceutically acceptable salt thereof.
 3. Acompound according to claim 2 wherein all of R_(c) or all of R_(c') areH.
 4. A compound according to claim 2 wherein u is 0, n is 1 and x is 1.5. A compound according to claim 4 wherein one of R₁, R₂, and R₃ in##STR229## moiety of formula I is H.
 6. A compound according to claim 2having the formula ##STR230## wherein R₄ is phenyl or ##STR231##
 7. Acompound according to claim 6 wherein m₂ is 0 and n₂ is
 1. 8. A compoundaccording to claim 2, wherein n is 0 to
 2. 9. A compound selected fromthe group consisting of ##STR232## wherein Z is ##STR233## or apharmaceutically acceptable salt thereof; and ##STR234## wherein Z is##STR235## or a pharmaceutically acceptable salt thereof.
 10. Acomposition comprising a neurokinin antagonistic effective amount of acompound according to claim 2 and a pharmaceutically acceptable carriermaterial.
 11. A method for inducing neurokinin antagonism whichcomprises administering a neurokinin antagonistic effective amount of acompound according to claim 2 to a mammal in need thereof.
 12. A methodfor treating asthma or bronchospasm comprising administering to a mammalin need of such treatment a neurokinin antagonistic effective amount ofa compound of claim 2.